Bioinformatics analysis of oxidative stress genes in the pathogenesis of ulcerative colitis based on a competing endogenous RNA regulatory network.

Background: Ulcerative colitis (UC) is a common chronic disease associated with inflammation and oxidative stress. This study aimed to construct a long noncoding RNA (lncRNA)-microRNA (miRNA)-messenger RNA (mRNA) network based on bioinformatics analysis and to explore oxidative stress-related genes underlying the pathogenesis of UC. Methods: The GSE75214, GSE48959, and GSE114603 datasets were downloaded from the Gene Expression Omnibus database. Following differentially expressed (DE) analysis, the regulatory relationships among these DERNAs were identified through miRDB, miRTarBase, and TargetScan; then, the lncRNA-miRNA-mRNA network was established. The Molecular Signatures Database (MSigDB) was used to search oxidative stress-related genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed for functional annotation and enrichment analyses. Based on the drug gene interaction database DGIdb, drugs that interact with oxidative stress-associated genes were explored. A dextran sulfate sodium (DSS)-induced UC mouse model was used for experimental validation. Results: A total of 30 DE-lncRNAs, 3 DE-miRNAs, and 19 DE-mRNAs were used to construct a lncRNA-miRNA-mRNA network. By comparing these 19 DE-mRNAs with oxidative stress-related genes in MSigDB, three oxidative stress-related genes (CAV1, SLC7A11, and SLC7A5) were found in the 19 DEM sets, which were all negatively associated with miR-194. GO and KEGG analyses showed that CAV1, SLC7A11, and SLC7A5 were associated with immune inflammation and steroid hormone synthesis. In animal experiments, the results showed that dexamethasone, a well-known glucocorticoid drug, could significantly decrease the expression of CAV1, SLC7A11, and SLC7A5 as well as improve UC histology, restore antioxidant activities, inhibit inflammation, and decrease myeloperoxidase activity. Conclusion: SLC7A5 was identified as a representative gene associated with glucocorticoid therapy resistance and thus may be a new therapeutic target for the treatment of UC in the clinic.

Paeoniflorin improves ulcerative colitis via regulation of PI3K­AKT based on network pharmacology analysis.

Paeoniflorin (PF) is the primary component derived from Paeonia lactiflora and white peony root and has been used widely for the treatment of ulcerative colitis (UC) in China. UC primarily manifests as a chronic inflammatory response in the intestine. In the present study, a network pharmacology approach was used to explore the specific effects and underlying mechanisms of action of PF in the treatment of UC. A research strategy based on network pharmacology, combining target prediction, network construction, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and molecular docking simulation was used to predict the targets of PF. A total of 288 potential targets of PF and 599 UC-related targets were identified. A total of 60 therapeutic targets of PF against UC were identified. Of these, 20 core targets were obtained by protein-protein interaction network construction. GO and KEGG pathway analyses showed that PF alleviated UC through EGFR tyrosine kinase inhibitor resistance, the IL-17 signaling pathway, and the PI3K/AKT signaling pathway. Molecular docking simulation showed that AKT1 and EGFR had good binding energy with PF. Animal-based experiments revealed that the administration of PF ameliorated the colonic pathological damage in a dextran sulfate sodium-induced mouse model, resulting in lower levels of proinflammatory cytokines including IL-1ß, IL-6, and TNF-α, and higher levels of IL-10 and TGF-ß. PF decreased the mRNA and protein expression levels of AKT1, EGFR, mTOR, and PI3K. These findings suggested that PF plays a therapeutic protective role in the treatment of UC by regulating the PI3K/AKT signaling pathway.

Relationship between honesty-credit, specialty identity, career identity, and willingness to fulfill the contract among rural-oriented tuition-waived medical students of China: a cross-sectional study.

Background: The fulfillment of contractual obligations by rural-oriented tuition-waived medical students (RTMSs) to work in rural medical institutions after graduation directly impacts the improvement of rural health quality. This study aimed to not only quantitatively measure the direct impact of honesty-credit, specialty identity, and career identity on willingness to fulfill the contract of RTMSs but also to quantify the intermediary role of specialty identity and career identity between honesty-credit and willingness to fulfill the contract. The research results provided recommendations for the rural-oriented tuition-waived medical education (RTME) program to achieve its goal of training rural primary healthcare personnel. Methods: From March to May 2022, 1162 RTMSs were selected as the research objects. The honesty-credit, specialty identity, career identity, and willingness to fulfill the contract were quantitated using a self-completed questionnaire. Pearson's correlation analysis and structural equation modeling were used for statistical analysis and mediating effect evaluation. Results: A total of 455 (42.3%) RTMSs had high willingness to fulfill the contract, and honesty-credit had a significant direct positive effect on willingness (ß = 0.198, P < 0.001), specialty identity (ß = 0.653, P < 0.001), and career identity (ß = 0.180, P < 0.001). In the intermediary path between honesty-credit and willingness, career identity [95% confidence interval (CI): 0.007-0.051] had significant mediating effects. Career identity (95% CI: 0.030-0.149) also had significant mediating effects between specialty identity and willingness, and specialty identity (95% CI: 0.465-0.760) had significant mediating effects between honesty-credit and career identity. These results strongly confirmed that honesty-credit, specialty identity, and career identity are early and powerful predictors of the willingness to fulfill the contract of RTMSs. Conclusion: The honesty-credit of RTMSs can predict their willingness to fulfill the contract early, significantly and positively. For the students who fail to pass the credit assessment for many times and have a strong tendency to default, their training qualifications should be canceled in time, so that students who are truly willing to serve rural areas can enter the project, and finally achieve the policy goal of "strengthening the rural primary medical and health system".

Molecular Targets and Mechanisms of Scutellariae radix-Coptidis rhizoma Drug Pair for the Treatment of Ulcerative Colitis Based on Network Pharmacology and Molecular Docking.

This study aims to analyze the targets of the effective active ingredients of Scutellariae radix-Coptidis rhizoma drug pair (SCDP) in ulcerative colitis (UC) by network pharmacology and molecular docking and to explore the associated therapeutic mechanism. The effective active ingredients and targets of SCDP were determined from the TCMSP database, and the drug ingredient-target network was constructed using the Cytoscape software. The disease targets related to UC were searched in GeneCards, DisGeNET, OMIM, and DrugBank databases. Then, the drug ingredient and disease targets were intersected to construct a protein-protein interaction network through the STRING database. The Metascape database was used for the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of the predicted targets of SCDP for UC. The Autodock software was used for molecular docking between the main active ingredient and the core target to evaluate the binding ability. SCDP has 43 effective active ingredients and 134 intersection targets. Core targets included AKT1, TP53, IL-6, VEGFA, CASP3, JUN, TNF, MYC, EGFR, and PTGS2. GO functional enrichment analysis showed that biological process was mainly associated with a cytokine-mediated signaling pathway, response to an inorganic substance, response to a toxic substance, response to lipopolysaccharide, reactive oxygen species metabolic process, positive regulation of cell death, apoptotic signaling pathway, and response to wounding. KEGG enrichment analysis showed main pathway concentrations were related to pathways in cancer, AGE-RAGE signaling pathway in diabetic complications, bladder cancer, IL-17 signaling pathway, apoptosis, p53 signaling pathway, and PI3K-Akt signaling pathway. The drug active ingredient-core target-key pathway network contains 41 nodes and 108 edges, of which quercetin, wogonin, baicalein, acacetin, oroxylin A, and beta-sitosterol are important active ingredients; PTGS2, CASP3, TP53, IL-6, TNF, and AKT1 are important targets; and the pathways involved in UC treatment include pathways in cancer, PI3K-Akt signaling pathway, AGE-RAGE signaling pathway in diabetic, apoptosis, IL-17 signaling pathway and herpes simplex infection. The active ingredient has a good binding capacity to the core target. SCDP key active ingredients are mainly quercetin, wogonin, baicalein, acacetin, oroxylin A, and beta-sitosterol, which function mainly by regulating targets, such as PTGS2, CASP3, TP53, IL-6, TNF, and AKT1, and are associated with multiple signaling pathways as pathways in cancer, PI3K-Akt signaling pathway, apoptosis, IL-17 signaling pathways.

Based on Network Pharmacology to Explore the Molecular Targets and Mechanisms of Gegen Qinlian Decoction for the Treatment of Ulcerative Colitis.

BACKGROUND: Gegen Qinlian (GGQL) decoction is a common Chinese herbal compound for the treatment of ulcerative colitis (UC). In this study, we aimed to identify its molecular target and the mechanism involved in UC treatment by network pharmacology and molecular docking. Material and Methods. The active ingredients of Puerariae, Scutellariae, Coptis, and Glycyrrhiza were screened using the TCMSP platform with drug-like properties (DL) ≥ 0.18 and oral availability (OB) ≥ 30%. To find the intersection genes and construct the TCM compound-disease regulatory network, the molecular targets were determined in the UniProt database and then compared with the UC disease differential genes with P value < 0.005 and ∣log2 (fold change) | >1 obtained in the GEO database. The intersection genes were subjected to protein-protein interaction (PPI) construction and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. After screening the key active ingredients and target genes, the AutoDock software was used for molecular docking, and the best binding target was selected for molecular docking to verify the binding activity. RESULTS: A total of 146 active compounds were screened, and quercetin, kaempferol, wogonin, and stigmasterol were identified as the active ingredients with the highest associated targets, and NOS2, PPARG, and MMP1 were the targets associated with the maximum number of active ingredients. Through topological analysis, 32 strongly associated proteins were found, of which EGFR, PPARG, ESR1, HSP90AA1, MYC, HSPA5, AR, AKT1, and RELA were predicted targets of the traditional Chinese medicine, and PPARG was also an intersection gene. It was speculated that these targets were the key to the use of GGQL in UC treatment. GO enrichment results showed significant enrichment of biological processes, such as oxygen levels, leukocyte migration, collagen metabolic processes, and nutritional coping. KEGG enrichment showed that genes were particularly enriched in the IL-17 signaling pathway, AGE-RAGE signaling pathway, toll-like receptor signaling pathway, tumor necrosis factor signaling pathway, transcriptional deregulation in cancer, and other pathways. Molecular docking results showed that key components in GGQL had good potential to bind to the target genes MMP3, IL1B, NOS2, HMOX1, PPARG, and PLAU. CONCLUSION: GGQL may play a role in the treatment of ulcerative colitis by anti-inflammation, antioxidation, and inhibition of cancer gene transcription.

[Clinical Trials of Slow-rapid Reinforcing-reducing Needling Manipulation at Jiaji (EX-B 2) Acupoint for Lumbar Intervertebral Disc Protrusion].

OBJECTIVE: To observe the clinical effect of slow-rapid reinforcing-reducing needling manipulation at Jiaji (EX-B 2) acupoint for lumbar intervertebral disc protrusion. METHODS: Sixty subjects met the inclusion criteria of disc herniation were randomly divided into treatment group (n = 30) and control group (n = 30). In the treatment group, the stimulation mode (slow or fast, reinforcement or reduction) of Jiaji acupoints (EX-B 2) was based on the status of the patients by an overall analysis of symptoms and signs. Other acupoints such as Huantiao (GB 30), Weizhong (BL 40), etc. were stimulated with uniform reinforcing-reducing manipulation. In the control group, all the acupoints were stimulated in uniform reinforcing-reducing mode. The treatment was conducted once a day, continuously for 18 days with 1 day's break between every 6 days. The clinical efficacy appraisal, visual analogue scale (VAS) and Japanese orthopaedic association (JOA) scores and traditional Chinese medicine (TCM) syndrome scores were used for outcome assessment. RESULTS: In comparison with pretreatment, the VAS scores and TCM syndrome scores were significantly decreased in both control and treatment groups (P<0. 05), and the JOA scores were markedly increased after the treatment (P<0. 05). The therapeutic effects of the treatment group were obviously superior to those of the control group in down-regulating the VAS score and TCM syndome score and up-regulating JOA score (P<0. 05). CONCLUSION: Slow-fast reinforcing-reducing needling manipulation is superior to the routine acupuncture in the management of lumbar intervertebral disc protrusion.